The Effect of Botulinum-A Toxin in Incontinent Children With Therapy Resistant Overactive Detrusor P. Hoebeke,* K. De Caestecker, J. Vande Walle, J. Dehoorne, A. Raes, P. Verleyen and E. Van Laecke From the Departments of Pediatric Urology and Pediatric Nephrology (JVW, JD, AR), Ghent University Hospital, Gent, Belgium
Purpose: We determined the effect of detrusor injection of botulinum-A toxin in a cohort of children with therapy resistant nonneurogenic detrusor overactivity. This prospective study included therapy resistant children with overactive bladder. Material and Methods: During the study period of 19 months 10 boys and 11 girls were included. All patients showed decreased bladder capacity for age, urge and urge incontinence. Main treatment duration before inclusion was 45 months. A dose of 100 U botulinum-A toxin (Botox®) was injected in the detrusor. Results: Side effects were evaluated in all 21 included patients. The side effects reported were 10-day temporary urinary retention in 1 girl and signs of vesicoureteral reflux with flank pain during voiding in 1 boy, which disappeared spontaneously after 2 weeks. No further examinations were done since the boy refused. Two girls experienced 1 episode each of symptomatic lower urinary tract infection. Eight girls and 7 boys with a minimum followup of 6 months represent the study group for long-term evaluation. In this study group after 1 injection 9 patients showed full response (no more urge and dry during the day) with a mean increase in bladder capacity from 167 to 271 ml (p ⬍0.001). Three patients showed a partial response (50% decrease in urge and incontinence) and 3 remained unchanged. Eight of the 9 full responders were still cured after 12 months, while 1 of the initially successfully treated patients had relapse after 8 months. The 3 partial responders and the patient with relapse underwent a second injection with a full response in the former full responder and in 1 partial responder. Conclusions: Botulinum-A toxin injection in children with nonneurogenic overactive detrusor is an excellent treatment adjunct, leading to long-term results in 70% after 1 injection. Key Words: bladder; urinary incontinence; botulinum toxin type A; muscle, smooth; child
knowledge the first experience with botulinum-A toxin in a pediatric population with nonneurogenic overactive bladder.
otulinum-A toxin is a potent neurotoxin that blocks neuronal acetylcholine secretion by binding to presynaptic nerve endings. Intramuscular injection of botulinum-A toxin blocks the neuromuscular junction at the site of injection until new presynaptic nerve sprouts occur. Initially used to treat striated muscle overactivity, increasing data in the literature are available on its effectiveness for acetylcholine stimulated smooth muscle overactivity, as in the lower urinary tract. Botulinum-A toxin is used in adult urology to treat neurogenic detrusor overactivity, chronic urinary retention, detrusor-sphincter dyssynergia, nonneurogenic detrusor overactivity and chronic prostatic pain.1 Recent studies show high short-term effectiveness for idiopathic detrusor overactivity in adults.2 In children it has been safely used to treat strabismus, muscular hypertonia due to cerebral palsy and neurogenic detrusor overactivity in those with myelomeningocele.3,4 Due to the high prevalence of overactive detrusor in the pediatric population, the known effect on overactivity in adults and safety in a pediatric population we designed a prospective study. We report the results of what is to our
B
MATERIALS AND METHODS A prospective protocol was designed for the use of botulinum-A toxin in children with urodynamically proven detrusor overactivity without overt neuropathy or uropathy. Urodynamics considered for inclusion had to be performed within 2 months before inclusion. Methods conform to the standards and recommendations for urodynamic studies of the International Continence Society.5 Children who had previously been treated without success were considered for inclusion. Children with dysfunctional voiding or post-void residual urine were excluded. The study was approved by the ethics committee of the Ghent University Hospital. Subjects and their parents provided informed consent. Treatment was done with the patient under general anesthesia. A dose of 100 U botulinum-A toxin (Botox®) was diluted in 15 ml normal saline. Under cystoscopic guidance the detrusor was injected at 15 sites with 1 ml injected per site. A 3.7Fr Deflux® injection needle was used. Injection was started above the superior edge of the trigone and a line of 5 injections was given with each injection 1 cm apart. Two more lines 1 cm cranial from the former line were injected subsequently. The ventral bladder wall was avoided due to its close relationship with the peritoneal cavity. After injection the bladder was emptied. After spontaneous voiding the patient was sent home.
Study received approval from the ethics committee of Ghent University Hospital. * Correspondence: Department of Pediatric Urology, Ghent University Hospital, De Pintelaan 185, B 9000 Gent, Belgium (e-mail:
[email protected]).
0022-5347/06/1761-0328/0 THE JOURNAL OF UROLOGY® Copyright © 2006 by AMERICAN UROLOGICAL ASSOCIATION
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Vol. 176, 328-331, July 2006 Printed in U.S.A. DOI:10.1016/S0022-5347(06)00301-6
BOTULINUM-A TOXIN IN INCONTINENT CHILDREN WITH OVERACTIVE DETRUSOR The intent was to repeat urodynamics after injection. However, we encountered strong patient and parent obstruction. Most patients had undergone urodynamics during former treatments and just before study inclusion. Especially when the result was favorable, they refused followup urodynamics. Therefore, we excluded this from the protocol and considered a less invasive evaluation. Patients were seen after 1 week for uroflowmetry and post-void residual urine measurement. After 6 weeks patients were seen for clinical evaluation. A voiding diary was supposed to be kept for a few days. Six and 12 months after injection they were reevaluated. At each visit they were questioned about side effects and the effects of treatment. Outcome was measured by measuring bladder capacity and documenting urge and urge incontinence in the voiding diary. Nighttime continence was not used as an outcome measure. We called the result a complete response when no more daytime symptoms (urge and urge incontinence) were observed. A 50% decrease in urge and urge incontinence was called a partial response. No clinical improvement was called failure. Functional bladder capacity was documented and evaluated. However, it was not used as an outcome measure. RESULTS During a study period of 19 months starting May 2003, 10 girls and 11 boys were included. Mean age at study inclusion was 10.8 years (range 8 to 14). Based on voiding diaries all patients showed decreased bladder capacity for age, urge and urge incontinence before inclusion. All patients experienced nighttime incontinence. Constipation was seen in 7 patients. The diagnosis was overactive bladder in all cases. None of the patients showed dysfunctional voiding. The diagnosis was confirmed by urodynamic study before treatment. None of the patients showed post-void residual urine. Main treatment duration before inclusion was 45 months. Former treatment consisted of capacity training with antispasmodics or anticholinergics and urotherapy. All included children had been treated without success at the voiding school, which is 2-week in-hospital bladder training. A dose of 100 U botulinum-A toxin (Botox®) was injected in the detrusor with the patient under general anesthesia. The side effects reported were 10-day temporary urinary retention in 1 girl, temporary vesicoureteral reflux in 1 boy and lower urinary tract infection in 2 girls. No other side effects were seen. Eight girls and 7 boys with a minimum followup of 6 months formed the study group for long-term evaluation. After 1 injection 9 patients showed a full response (no more urge and dry during the day) with a mean increase in bladder capacity from 167 to 271 ml (61%) (p ⬍0.001). Three patients showed a partial response (decreased urge and incontinence) and 3 remained unchanged. Eight of the 9 full responders were still cured after 12 months. One patient had relapse after 8 months. The 3 partial responders and the patient with relapse underwent a second injection with a full response in the former full responder and in 1 partial responder. No further response was observed in 2 partial responders. On postoperative uroflowmetry no differences were seen except voided volume in most patients. Three girls and 1 boy
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had temporary dysfunctional characteristics on postoperative uroflowmetry. In 1 of these girls post-void ultrasound showed significant residual urine (greater than 50% of capacity). Minimal post-void residual urine (less than 5% of detrusor capacity) was seen in another 4 patients. After 6 weeks all patients voided to completion. DISCUSSION To our knowledge we report the first experience with botulinum-A toxin in a pediatric population with nonneurogenic detrusor overactivity. The first difference in the current data compared to results in the literature is the longer duration of the effect. In studies in adults it has been shown that the effect of botulinum-A toxin injection is temporary. In the current study a long-term effect of more than 12 months was seen in 8 of 15 patients. Former reports of use in children with neurogenic bladder demonstrate an effect that lasted 10 months.1,3,4,6 Perhaps the fact that the treatment was used for a disorder that is an expression of a maturation delay of detrusor function rather than a structural anomaly can account for this longer and better effect. Overactivity inhibition can allow detrusor function to mature. The dose of botulinum-A toxin used in the current study was selected rather arbitrarily. Concerning the dose, no clear guidelines are found in the literature. In children with neuropathic overactive bladder higher doses are used. Riccabona et al used 10 U/kg body weight to a maximum of 360 U,4 while Schulte-Baukloh et al preferred 12.5 U/kg body weight to a maximum of 300 U.3 Important and misleading for determining the dose is the fact that the different brands of botulinum-A toxin have different units. The 100 U used in the current study are only applicable to Botox®.7 As long as the dose does not exceed 300 U, it is unlikely that systemic weakness or paralysis would occur. Muscle weakness has been described in urological procedures in adults by some groups3,4 but to our knowledge it has never been mentioned in the treatment of children to date. Temporary autonomic side effects have been described but they mainly disappear after some weeks.6 In this study no systemic side effects were noted. It seems to be important to keep the injected volume as low as possible because the risk of systemic absorption and generalized weakness seems to be related more to the volume than to the quantity of botulinum-A toxin.6,8 In the current study 1 serious side effect was seen in 1 girl with a post-void residual urine volume of more than 50% of functional bladder capacity. She needed intermittent catheterization for 10 days, after which voiding normalized. It is even questionable if this retention was due only to the autonomic side effect of botulinum-A toxin or rather the result of a combination of detrusor-sphincter dyssynergia and the botulinum-A toxin effect. In our study we found that some children had a dysfunctional uroflow pattern some weeks after injection, which later disappeared. One boy had clinical vesicoureteral reflux with pain at the kidney site during voiding. The patient refused voiding cystography, so the diagnosis was not confirmed. The symptom disappeared after 2 weeks. Furthermore, 2 girls had a lower urinary tract infection after injection. These girls had normal uroflowmetry and emptied the bladder completely. Therefore, the infections might have been unrelated to botulinum-A toxin treatment.
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After this pilot study, which proves safety and long-term efficacy, some further studies are needed, especially in regard to the botulinum-A toxin dose. Possibly some children may need multiple injection and, therefore, defining the dose is important. With repeat injections it is known that resistance develops to the toxin in some patients. Humans may form antibodies to botulinum-A neurotoxin or to associated nontoxin proteins.6,9 It has been shown that shorter intervals between doses and higher doses contribute to the development of resistance.10 Therefore, it is recommended to avoid booster injections, leave at least a 3-month interval between 2 treatments and use the smallest clinically effective dose.11 The latter is probably the most challenging factor because the dose used today in children is still determined rather empirically. In our view the clinically effective dose is less influenced by the body weight of the child than by bladder properties, such as bladder mass and detrusor compliance. We postulate that the thicker the bladder wall, as estimated on ultrasound, the more muscle mass and the higher the dose needed to have a long lasting effect. As in the treatment of neuropathic overactive bladder but probably also in some children with nonneuropathic overactive bladder, several repeat injections are necessary. An adequate method of determining the clinically effective dose should be developed to avoid elimination of this valuable treatment due to resistance. In the current study it seems that a partial response was a poor prognostic factor for repeating the injection. Three partial responders underwent repeat injection but only 1 responded. One full responder who had relapse showed a new full response after a second injection. Thus, probably a full response after the first injection is a good prognostic factor for further injection therapy. Repeat injections seem to be as safe and effective as the first injection.12 Before botulinum-A toxin injection therapy can be used as a primary therapy for overactive detrusor in childhood further research is necessary. Most evidence could be gathered in a placebo controlled study. However, to our knowledge the industry shows no interest in the development of such a protocol. Further clinical trials are needed to confirm the results of this pilot study. CONCLUSIONS The use of botulinum-A toxin for nonneurogenic overactive bladder in children who are resistant to common treatments is a safe and effective treatment modality. Standardization of this therapy, especially concerning the optimal clinical effective dose, must be done if we want to keep this therapeutic tool effective in the long term. REFERENCES 1.
2.
3.
Leippold, T., Reitz, A. and Schurch, B.: Botulinum-A toxin as a new therapy option for voiding disorders: current state of the art. Eur Urol, 44: 165, 2003 Flynn, M. K., Webster, G. D. and Amundsen, C. L.: The effect of botulinum-A toxin on patients with severe urge urinary incontinence. J Urol, 172: 2316, 2004 Schulte-Baukloh, H., Michael, T., Schobert, J., Stolze, T. and Knispel, H. H.: Efficacy of botulinum-A toxin in children with detrusor hyperreflexia due to myelomeningocele: preliminary results. Urology, 59: 325, 2002
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Riccabona, M., Koen, M., Schindler, M., Goedele, B., Pycha, A., Lusuardi, L. et al: Botulinum-A toxin injection into the detrusor: a safe alternative in the treatment of children with myelomeningocele with detrusor hyperreflexia. J Urol, 171: 845, 2004 Abrams, P., Cardozo, L., Fall, M., Griffiths, D., Rosier, P., Ulmsten, U. et al: The standardisation of terminology in lower urinary tract function: report from the Standardisation Sub-Committee of the International Continence Society. Standardisation Sub-Committee of the International Continence Society. Urology, 61: 37, 2003. Smith, C. P. and Chancellor, M. B.: Emerging role of botulinum toxin in the management of voiding dysfunction. J Urol, 171: 2128, 2004 Brin, M. F. and Blitzer, A.: Botulinum-A toxin: dangerous terminology errors. J R Soc Med, 86: 493, 1993 Kim, H. S., Hwang, J. H., Jeong, S. T., Lee, Y. T., Lee, P. K., Suh, Y. L. et al: Effect of muscle activity and botulinum-A toxin dilution volume on muscle paralysis. Dev Med Child Neurol, 45: 200, 2003 Dolimbek, B. Z., Jankovic, J. and Atassi, M. Z.: Cross reaction of tetanus and Botulinum neurotoxins A and B and the boosting effect of botulinum neurotoxins A and B on primary anti-tetanus antibody response. Immunol Invest, 31: 247, 2002 Jankovic, J. and Schwartz, K.: Response and immunoresistance to botulinum-A toxin injections. Neurology, 45: 1743, 1995 Brin, M. F.: Botulinum-A toxin: chemistry, pharmacology, toxicity and immunology. Muscle Nerve Suppl, 6: S146, 1997 Grosse, J., Kramer, G. and Stohrer, M.: Success of repeat detrusor injections of botulinum a toxin in patients with severe neurogenic detrusor overactivity and incontinence. Eur Urol, 47: 653, 2005
EDITORIAL COMMENT The use of botulinum-A toxin was pioneered by Schurch et al in 2000 by applying the toxin into the neurogenic overactive detrusor and by that achieving increased bladder capacity and decreased pressures.1 The first child to receive botulinum-A toxin for a neurourological condition was a 7-year-old girl with upper tract dilatation.2 Since then, the overall use in children with a urological condition has concentrated on treating neurogenic overactive bladder. In adults the indications for treatment with botulinum-A toxin have now expanded to other urological conditions, eg urinary incontinence and voiding disorders. Evidently this trend will be reproduced in children. Therefore, it is important to bear in mind that overactive bladder in most children is a dynamic condition, as opposed to the static overactive bladder in adults. This fact should be taken into account when considering this treatment. At this point no major short-term or long-term adverse effects have been described in children. Besides the generalized effect and antibody production, the primary risk is that injection of the toxin may create irreversible long-term side effects, eg ultrastructural and functional changes of the detrusor. This would probably only be revealed after a longer period of use. Reports of long-term followup with repeat injections in the bladder of children through puberty are nonexisting and a few short-term reports are based on retrospective studies. Schulte-Baukloh et al recently reported a study of repeat injections of botulinum-A toxin in children with neurogenic
BOTULINUM-A TOXIN IN INCONTINENT CHILDREN WITH OVERACTIVE DETRUSOR detrusor overactivity.3 As in similar studies, this study shows increased capacity, decreased pressure and increased bladder compliance. The current series is the first to explore the effectiveness of injecting botulinum toxin into the detrusor in children with nonneurogenic overactive bladder. They observed impressive results in a select, hard core group of children with continuing incontinence after what modern combined therapy could offer. The investigators injected a standard dose of 100 U botulinum-A toxin into the detrusor. This is interesting since the recommended dose in children is 10 to 12 U/kg body weight (maximum 300 U). Since this is not based on evidence but taken from the dose used in pediatric neurology, this should be further evaluated. Unfortunately, as in many other studies in children, intent to treat has replaced the randomized, controlled clinical trial. Future studies including randomization, controls and long-term followup are mandatory before this treatment for
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nonneurological bladder dysfunction is taken into daily clinical use. Bettina Jørgensen Institute of Clinical Medicine University of Aarhus Aarhus, Denmark 1.
Schurch, B., Stohrer, M., Kramer, G., Schmid, D. M., Gaul, G. and Hauri, D.: Botulinum toxin A for treating detrusor hyperreflexia in spinal cord injured patients: a new alternative to anticholinergic drugs. J Urol, 164: 692, 2000 2. Steinhardt, G. F., Naseer, S. and Cruz, O. A.: Botulinum toxin: novel treatment for dramatic urethral dilation associated with dysfunctional voiding. J Urol, 158: 190, 1997 3. Schulte-Baukloh, H., Knispel, H. H., Stolze, T., Weiss, C., Michael, T. and Miller, K.: Repeated botulinum-A toxin injections in treatment of children with neurogenic detrusor overactivity. Urology, 66: 865, 2005